Angiotensin converting enzyme (ACE) is a zinc metalloproteinase, and a carboxyl dipeptidase, which is one of the important proteases in the renin-angiotensin system. The ACE plays an important role in the regulation of human blood pressure. It removes His-Leu by acting on the terminal of angiotensin I to produce angiotensin II, which allows contraction of arterial smooth muscle, causing rapid rise in blood pressure. An effective method of lowering the blood pressure is inhibiting the ACE activity. Current pharmaceuticals for treatment of high pressure are mostly synthetic chemicals, which have certain adverse effects, such as cough, taste disorders, rashes and other side effects. Thus ACE inhibitory peptides prepared from food-borne proteins as raw material represent an important direction for the development of antihypertensive pharmaceuticals due to the high level of safety, low level of toxic or side effects and other advantages thereof.
Short peptides are easy to prepare, and substantially have no side effects on the human body. Researches show that, a short peptide with specific structure, for example, dipeptide, tripeptide and tetrapeptide, has certain inhibitory effect on the activity of ACE, which makes the short peptide an ACE enzyme inhibitor having a broad development prospect.
LIU Huan, LE Guowei, SHI Yonghui, et al. Structure-activity relationship of angiotensin converting enzyme dipeptide inhibitors [J]. Computers and Applied Chemistry, 2006, 22(8):631-635 discloses that a model of structure-activity relationship of angiotensin converting enzyme dipeptide inhibitors is established from the primary structures of peptide chains, by taking molecular electro-negativity edge vector (MEEV) as a parameter, and taking 36 angiotensin converting enzyme dipeptide inhibitors as samples. The rule of “distance of two, five, and seven chemical bond” inhibitory enzyme activity of dipeptide bond is obtained by means of model analysis, said rule means: (1) the carboxyl of the peptide bond forms two-ligand with Zn atom, which is stabilized by the H-bond formed between the N-atom and the carboxyl oxygen of the peptide bond; (2) the five-bond structure unit is formed between the carboxylate radical group acting with Arg (Arginine) positive charged salt bond in the ACE enzyme and the amino group of the second amino acid to play a key role in antihypertensive effect; and (3) the amino group of the peptide bond in the dipeptide inhibitor containing an aromatic amino acid shows trans configuration with the hydroxyl terminal of the benzene ring portion, with seven bonds between them.
LIU Jing, PENG Jianqiu, and GUAN Xiao. Modeling study on quantitative structure-activity relationship of angiotensin converting enzyme inhibitory peptides based on multiple linear regression [J]. Journal Analytical Science, 2012, 28(001):16-22 discloses that a multiple linear regression (MLR) model of structure and activity is established using an amino acid structure describer SVHEHS to characterize dipeptide, tripeptide and tetrapeptide sequences competitively inhibiting Angiotensin Converting Enzyme (ACE), respectively. The correlation coefficient, cross validation correlation coefficient, root mean square error and external validation correlation coefficient are respectively 0.851, 0.781, 0.327, and 0.792 for the ACE inhibitory dipeptide model; respectively 0.805, 0.717, 0.339, and 0.817 for the tripeptide model; and respectively 0.792, 0.553, 0.393, and 0.630 for the tetrapeptide model.
According to Liu Huan. Research on ACE inhibitory peptides in rice [D]. Jiangnan University, 2005, a model for structure-activity relationship of angiotensin converting enzyme dipeptide inhibitors is established by taking molecular electro-negativity edge vector (MEEV) as a parameter, and taking 36 angiotensin converting enzyme dipeptide inhibitors as samples. The model analysis shows that hydrophobic amino acids, for example, aromatic amino acids and branched-chain amino acids at C-terminal, are key factors affecting ACE inhibitory activity.
The results disclosed in LIU Jing, GUAN Xiao, PENG Jianqiu. QSAR study on ACE inhibitory peptide based on amino acid descriptor SVHEHS [J] Acta Chimica Sinica, 2012, 70(1):83-91 show that the hydrophobicity (X15), electrical property (X17), and stereoscopic feature (X24) of C-terminal amino acid, as well as stereoscopic feature (X12) of N-terminal amino acid of the dipeptide are highly correlated to the activity of the peptide.
The results disclosed in PENG Jianqiu. Research on quantitative structure-activity relationship of ACE inhibitory peptide [D]. University of Shanghai for Science and Technology, 2012 demonstrate a dipeptide model with R2=0.851, RMSE=0.327, Q2LOO=0.781, Q2ext=0.792, and the hydrophobicity and charge property of the C-terminal amino acid residue and the stereoscopic property of the N-terminal amino acid residue have a relatively strong influence on the activity of an ACE inhibitory dipeptide, particularly, the strong hydrophobicity and weak charge property of the C-terminal amino acid residue have a positive effect on the activity of an ACE inhibitory dipeptide; and the hydrophobicity, electrical property, and stereoscopic property of C-terminal amino acid residue, and the stereoscopic property of N-terminal amino acid residue are highly correlated with the activity of a peptide.
In prior art, short peptides inhibiting ACE activity are researched from multiple perspectives in an attempt to determine the relationship between the structure of a short peptide and the ACE inhibitory activity. However, the results of the existing researches have limitations in that the accuracy of the predicted results is not high, and no dipeptide with high ACE inhibitory activity is found.
Developing a dipeptide with a high inhibitory activity is of great practical significance.